ABSTRACT Genome maintenance systems in complex organisms act to promote cell survival at the cost of occasional mutations as a consequence of repair or replication errors. When DNA damage levels are high, these systems can induce apoptosis or cellular senescence to prevent a high mutation load, the most serious consequence of which is cancer. Hence, genome maintenance systems protect organisms at early ages when the impact of losing proliferative cells to apoptosis or senescence is low. However, at later ages the impact of accumulating mutations, depleting cells through apoptosis, and accumulating non-dividing, pro-inflammatory senescent cells is high. Therefore, genome maintenance systems and their sequelae are another example of antagonistic pleiotropy. Importantly, this balancing act can be manipulated, as demonstrated by various conditions that extend life span, including dietary restriction, somatotrophic restraint and possibly the microRNA-mediated cell preservation response. In this renewal application, we propose to further characterize the pro-aging effects of DNA damage and explore if human extreme longevity and healthy aging can be related to exceptional genome maintenance. Based on the results we will then use premature aging mouse models to develop and test novel interventions that promote healthy aging and longevity. The results should clarify the relationships in humans and mice between specific defects in genome maintenance and aging phenotypes, better define proximal end points of aging driven by DNA damage and cellular damage responses in humans and mice and lead to molecular and cellular interventions that alleviate genotoxic stress and/or improve genome maintenance. Based on a wealth of evidence suggesting a causal relationship between adverse health effects associated with aging and DNA damage responses, this PPG application is designed to resolve the complex web of cause and effect relationships between DNA damage and aging, establish clear links between human and mouse DNA damage responses, and explore logical routes to modify these responses to ameliorate genome degeneration and its adverse health effects.